Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland. The exact function of the hormone in adult human beings has not been determined. In healthy young adults, melatonin is secreted as a broad pulse during nighttime sleep in the total amount of approximately 25-30 .mu.g per night, producing peak plasma concentrations of approximately 70 pg/ml, occurring at approximately 0200 h. Melatonin is secreted into the blood stream and possibly also into cerebrospinal fluid (CSF) simultaneously. The CSF/plasma concentration ratio is 1.0 or less. The terminal plasma elimination half-life is approximately 45 minutes; volume of distribution is approximately 40 liters; and the metabolic clearance of melatonin is approximately 1 liter per minute. The melatonin circadian (.about.24 hr) rhythm is thought to be driven by the same central nervous system oscillator that drives the daily rhythms of cortisol, urine volume, and core temperature (Shanahan and Czeisler, 1991), The relationship of the melatonin cycle to the activity/rest (sleep) cycle is not clear, but melatonin may organize the normal sleep pattern.
Melatonin has been administered to human beings orally and intranasally. It is readily absorbed through the gastrointestinal tract. The liver inactivates as much as 99% of the absorbed melatonin on the first-pass. Thus, the oral route of administration is inefficient and erratic.
Oral melatonin has been given to human beings to treat the phenomenon of "jet lag" following airplane trips associated with a change in time zones (Arendt et al. (1987) Ergonomics 30:1379-1393); U.S. Pat. Nos. 4,600,723 and 4,665,086). It has been given to patients with Parkinson's disease (Anton-Tay et al. (1971) Life Sciences 10:841-850), epilepsy (Anton-Tay et al., ibid.), or seasonal affective disorders (Wirz-Justice et al. (1990) J. Psychiat. Res. 24(2):129-137). It has been tried as a sleep-wake organizer in desynchronized blind persons (Arendt et al. (1988) Lancet pp 772-773; Folkard et al. (1990) Neuroscience Lett. 113:193-198; Sack et al., (1987) in, "Temporal Disorder in Human Oscillatory Systems", Eds. L. Rensing et al., Springer-Verlag, Heidelberg, pp 219-224; Sack and Lewy (1988) Am. Psychiatric Assoc. 141 Ann. Meeting, Montreal, Quebec). Improved timing of sleep cycles resulted. Oral melatonin has been given to insomniacs (Waldhouser et al. (1990) Psychopharmacology 100:222-226; Arendt et al. (1991) Lancet 337:1121-1124). Melatonin reduced the time awake before sleep onset and diminished sleep latency and number of awakenings. Overall sleep efficiency was increased, and mood, drive, alertness, and reaction time were improved the next day. Most of the published studies are consistent with the assumption that melatonin has mild sedative and hypnotic properties and may be a natural, sleep-inducing and sleep-organizing signal in humans. In addition, melatonin has been reported to lower intraocular pressure in glaucoma, to inhibit breast cancer (U.S. Pat. No. 4,855,305; Barch et al. (1991) Cancer 67:1681-1684), to be useful in the treatment of premenstrual depression (U.S. Pat. No. 4,945,103; Parry et al. (1990) Arch. Gen. Psychiatry 47:1139-1146; Yen et al. (1990) Arch. Gen. Psych. 47:1139-1146), for effecting contraception in humans (PCT Appln. WO 90/14084), and to prevent sudden infant death syndrome (Wurtman et al. (1990) Forensic Science Interntl. 45:171-180). Melatonin appears to be useful in animal husbandry by, for example, regulating the reproductive behavior of animal seasonal breeders (Reiter (1981) Endocr. Rev. 1:109-131; Nittman et al. (1983) Endocrinology 113:2276-2283; Arendt (1986) Oxford Reviews of Reproductive Biology 8:266-320) and regulating fur coat development in animals with seasonal variation.
Numerous analogs, homologs, agonists, antagonists and other compounds related to melatonin are known in the art, representatives of which are disclosed in, for example, U.S. Pat. No. 4,880,826, WO 87/00432, WO 89/01472, WO 89/04659, WO 90/14084, and EP 420 064, and by Frohn et al. (Life Sciences, Vol. 27, pp 2043-2046, Pergamon Press) and Clemens et al. (J. Neural Transm., (1986) (supp.) 21:451-459).
The transdermal route of administration for drugs and other biologically active agents ("agents") has been proposed for a wide variety of systemically acting and locally acting agents on either a rate-controlled or non rate-controlled basis and is described in numerous technical publications and patents, such as U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated herein by reference.
When first investigated in depth in the late 1960's, the transdermal route of administration of active agents appeared to offer many advantages, particularly with respect to agents that had short half-lives and a high degree of first-pass metabolism by the liver when orally administered. Presentation of the agent through the skin directly into the blood stream would eliminate "first-pass" metabolism of orally administered agents, which excludes the oral portal for some agents or requires extremely large oral doses for others.
In spite of intensive research and development activities by most of the major pharmaceutical companies on the potential candidates for transdermal administration, only six drugs are presently commercially available in the United States in the form of transdermal drug delivery devices: nitroglycerin, scopolamine, clonidine, estradiol, nicotine and fentanyl. This set is small because of difficulties inherent in the barrier properties of skin [see "Transdermal Drug Delivery: Problems and Possibilities", V. M. Knepp et al., CRC Critical Reviews and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1, (1987)].
The skin is a complex structure that performs its barrier function in several ways:
1. As a physical barrier having a relatively low permeability for most substances; PA1 2. As a sensory organ; PA1 3. As a metabolizing organ capable of converting some topically applied substances into metabolites. PA1 1. Skin permeability. The permeability of the agent through the skin must be sufficiently high so that it can be administered at therapeutically effective rates through an area of skin no greater than approximately 100 cm.sup.2 and preferably no greater than 50 cm.sup.2. The person-to-person variation in skin permeability at similar sites should also be relatively small. PA1 2. Skin binding. The skin beneath a transdermal delivery device has the potential capability of binding or dissolving a certain amount of agent. The amount of agent so bound must be supplied to the skin before the agent can be delivered into the blood stream at therapeutically effective rates. If large amounts of the agent are bound in the skin, significant delays in the onset of therapeutic effect ("lag time") will be observed, as well as corresponding delays in termination of effect upon removal of the device. Skin binding is not related to skin permeability. Agents that are highly permeable may also be highly bound, causing a lag time sufficiently long as to render them unsuitable for their intended use. PA1 3. Irritation. The skin reacts to many topically applied substances, particularly those maintained under occlusion, by blistering or reddening accompanied by unpleasant burning, itching, and stinging sensations. There is a wide inter-subject variation in susceptibility to irritation. An agent must be minimally irritating in a large percentage of the potential patient population in order to be suitable for safe and effective transdermal administration. PA1 4. Sensitization. Sensitization is an allergic reaction that is induced when an agent is first applied to the skin and is elicited upon continued exposure, which may occur immediately or after a long period of seemingly harmless exposure. The sensitization may be local, elicited by topical exposure, which manifests itself as contact dermatitis accompanied by blistering, itching, reddening, and burning at the site of application. More seriously, the sensitization may be systemic, elicited by topical application but manifesting itself by more general allergic reactions at sites other than the site of application. Most seriously, the systemic sensitization may be elicited by oral or intravenous administration of the drug. If the latter occurs, the patient will be unable to take the drug by any route of administration. PA1 5. Pharmacokinetic properties. The elimination half-life of an agent is the time after administration that half of the amount administered has been eliminated from the body. Blood concentrations of agents continuously administered at constant rates will continue to increase for approximately five half-lives before steady-state, constant blood concentrations are achieved. It is usually desirable that an agent have a relatively short half-life to be suitable for controlled, transdermal administration. When half-lives of agents determined from intravenous administration are compared with half-lives determined from transdermal administration, the transdermal half-lives are generally longer, but there can be wide variation in half-life among individuals based upon such factors as age, sex, health, and body type. The transdermal half-lives of most agents have not been determined. PA1 6. Pharmacodynamic properties. Constant blood levels may not produce the optimal therapeutic effects. For example, a therapeutic effect may only be observed at the peak blood concentration obtained from bolus dosing, but the peak concentration cannot be maintained because of side effects associated therewith. Also, continuous administration of many agents produces tolerance. Other cases may require either some agent-free interval or continually varying doses of the agent. PA1 7. Potency. Although a high potency is required for feasibility of transdermal administration of an agent, it is possible for an agent to be too potent. As potency increases, lower blood concentrations are required and much smaller total quantities are administered. Because of the normal inter-individual variations in skin permeability, it may not be possible to control precisely the dose a patient receives, and for potent agents with narrow "therapeutic windows," this uncertainty can be hazardous. Fortunately, in the present case, melatonin is relatively non-toxic. PA1 8. Metabolism. One of the perceived advantages of transdermal administration was that it avoided the "first-pass" metabolism of the agent by the liver which is associated with oral administration. It has now been recognized, however, that the skin, not the liver, is the largest metabolizing organ in the body. Thus, although first-pass metabolism which occurs after an orally adjusted agent enters the blood stream can be avoided, skin metabolism, which occurs before the agent enters the blood stream, must be dealt with. Skin metabolism is capable of creating metabolites which are inert, toxic or comparable in biological activity to that of the agent. An agent, to be suitable for transdermal administration, must have the metabolic properties that are consistent with its therapeutic use on continuous administration.
Thus, the transdermal route of administration, rather than being useful for every short half-life agent of high potency, has been found to be applicable only to a few agents possessing certain characteristics. The most significant of these considerations are:
There is a wide variation in allergic response among individuals as well as between sexes, races, and skin types. It is obvious that a useful transdermal agent must be minimally sensitizing in a large percentage of the potential patient population.
The above summarizes the primary characteristics recognized to date that affect suitability of an agent for transdermal administration. There are undoubtedly others, some of which have not yet been recognized. In order for an agent to be suitable for transdermal administration it must possess the right combination of all of these characteristics, a combination which, as illustrated by the very few drugs which are now known to be suitable for administration from transdermal delivery devices, is quite rare and unpredictable.